Inflammatory skin conditions are those conditions of the skin in which inflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes) infiltrate the skin with no overt or known infectious etiology. Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function. As used herein, inflammatory skin conditions include, but are not limited to, eczema and related conditions, insect bites, erythroderma, mycosis fungoides and related conditions, pyoderma gangrenosum, erythema multiforme, rosacea, onychomycosis, and acne and related conditions, but excluding psoriasis and its related conditions. The following is an overview of these inflammatory skin conditions.
I Eczema and Related Conditions
Eczema relates to a group of conditions characterized by varying degrees of itching, redness, scaling, and blistering of the skin. Eczema occurs as a reaction to many endogenous and exogenous agents, and is characterized in the acute stage by erythema, edema associated with a serious exudate between the cells of the epidermis and an inflammatory infiltrate in the dermis, oozing and vesiculation, crusting and scaling. Chronic stages are characterized by thickened skin areas with accentuated skin markings, signs of traumatized or abraded skin caused by scratching, and hyperpigmentation or hypopigmentation or both. The various types of eczema include the following:    i) Atopic eczema is the most common type of eczema. Atopic eczema is a chronic, pruritic, superficial inflammation of the skin, frequently associated with a personal or family history of allergic disorders such as hay fever and asthma. Topical or oral corticosteroids, or antihistamines are common treatments.    ii) Acrodermatitis continua is characterized by painful, often disabling, lesions on the fingertips or the tips of the toes. The nails may become deformed, and the disease can damage bone in the affected area. Treatment may include topical corticosteroids and systemic remedies, such as retinoids or psoralen-UVA, although is difficult due to the rarity of the disease.    iii) Contact allergic dermatitis is acute or chronic dermatitis caused by materials or substances coming into contact with the skin, which may involve either allergic or nonallergic mechanisms. Materials or substances known to induce contact allergic dermatitis include plant substances such as poison ivy, metals such as nickel or chromium, cosmetics, rubber compounds or chemicals.    iv) Contact irritant dermatitis is a nonallergic type of contact dermatitis caused by intense or long term exposure to a substance which directly damages the skin. Following exposure, skin inflammation can occur immediately or gradually after repeated exposure; for example, sunburn caused by overexposure to ultraviolet light; or exposure to acids and alkalis in household cleaning products.    v) Dyshydrotic eczema or pompholyx is a chronic condition characterized by deep-seated pruritic vesicles on the palms, sides of the fingers, and soles. Scaling, redness, and oozing often follow vesiculation. Secondary infection with Staphylococcal bacteria is frequent. Treatments include topical steroids and cold compresses, or oral steroids for acute cases.    vi) Lichen simplex chronicus is a chronic, superficial, pruritic inflammation of the skin, characterized by dry, scaling, well-demarcated, hyperpigmented, thickened skin with accentuated markings of oval, irregular, or angular shape. The pruritus may be controlled most effectively with topical corticosteroids.    vii) Nummular eczema is characterized by discrete, coin-shaped, ringed or annular lesions which may coalesce to form extensive patches, which may ooze and crust over, and affects the extensor surfaces of the extremities, lower legs, chest, back and buttocks. No treatment is uniformly effective. Oral antibiotics or corticosteroid creams are generally used as treatments. In more resistant cases, ultraviolet B radiation alone or ultraviolet A with oral psoralen may be helpful.    viii) Seborrheic dermatitis is chronic and characterized by moderate erythema; dry, moist or greasy scaling; itching; and yellow crusted patches on areas of the body with high densities of large oil glands, especially the face and scalp. Treatment with zinc pyrithione, selenium sulfide, sulfur and salicylic acid, tar shampoo, or a corticosteroid lotion is common.    ix) Stasis eczema is a chronic inflammation of the skin of the lower legs, commonly associated with venous incompetency. Edema, erythema, mild scaling, and brown discoloration occur. Elevating the ankle above the heart while resting, wearing properly fitted support hose, and applying topical therapy are necessary. However, unless circulation improves, these approaches will be relatively ineffective. The choice of topical therapy depends upon the disease stage, with therapies including compresses, dressings, and corticosteroid creams.II Insect Bites
Insect bites or stings can produce localized pain, redness, swelling and itching of the skin. In serious cases, complications include allergic reaction, infection, disease, reaction to venom, toxic reaction, or shock. Depending upon the specific insect, treatments may include rest and elevation, local application of ice packs and lotions, analgesics, antihistamines, or hospitalization for life threatening, anaphylactic reactions.
III Erythroderma
Erythroderma relates to any dermatitis where erythema (abnormal redness of the skin) occurs. Erythroderma, involving more than 90% of the skin, is potentially life threatening for a patient, since the barrier function of the skin has been lost. Hospitalization, topical moisturisers and intravenous fluids may be required to maintain hydration of the patient.
IV Mycosis Fungoides and Related Conditions
Mycosis fungoides is an uncommon chronic T-cell lymphoma primarily affecting the skin and occasionally the internal organs. Mycosis fungoides is rare, appearing as a chronic, pruritic rash which is difficult to diagnose. Initially plaquelike, it may spread to involve most of the skin, become nodular, and eventually become systemic. Lesions may become ulcerated. Pathologic diagnosis is delayed because sufficient quantities of lymphoma cells appear in the skin lesions very gradually. Treatment is temporarily effective, and may include psoralen-UVA, cortisone ointments for mild cases, nitrogen mustard, and photochemotherapy.
V Pyoderma Gangrenosum
Pyoderma gangrenosum is characterized by relatively indolent ulcers with extensive necrosis around the edges of the lesions on the lower extremities of the body. While pyoderma gangrenosum may be an isolated finding, it is most often associated with ulcerative colitis or Crohn's disease. The ulcers have ragged bluish-red overhanging edges and a necrotic base. The lesions often start as pustules or tender nodules at the site of trauma, and then gradually increase in size until liquefaction necrosis occurs and an irregular ulcer develops. The ulcers are often multiple and may cover large areas of the leg. Treatments include topical steroids, anti-inflammatory antibiotics, and oral steroids for more severe cases.
VI Erythema Multiforme
Erythema multiforme is an inflammatory eruption characterized by symmetric erythematous, edematous, or bullous lesions of the skin or mucous membranes. Erythema multiforme may be induced by an infectious disease (e.g., herpes simplex, Mycoplasma pneumoniae); drug therapy (e.g., penicillin, sulfonamides, and barbiturates); or a vaccine (e.g., Bacille Calmette-Guérin, poliomyelitis vaccines). The mechanism by which diseases, drugs, or vaccines cause erythema multiforme is unknown, but it is generally considered a hypersensitivity reaction. Treatments include mild topical cortisone, colloidal baths, and wet compresses.
VII Rosacea
Rosacea is a chronic inflammatory disorder, usually beginning in middle age or later and characterized by prominent cutaneous blood vessels, erythema, papules, and pustules primarily in the central areas of the face. Tissue hypertrophy, particularly of the nose, may result. Rarely, rosacea occurs on the trunk and extremities. The cause is unknown, but the disease is most common in persons with a fair complexion. Rosacea may resemble acne, but comedones are never present. Treatments include topical metronidazole for three months or oral antibiotics. Laser treatments may be required to remove tissue hypertrophy.
VIII Onychomycosis
Onychomycosis is an infection that causes fingernails or toenails to thicken, discolor, disfigure, and split. Thick toenails cause discomfort in shoes and make standing and walking painful for the patient. If the problem is caused by bacteria such as staphylococcus, streptococcus, and pseudomonas, the condition is called paronychia. In most cases, paronychia infections can be differentiated from onychomycosis by the inflammation they cause to the skin adjacent to the nail. Onychomycosis is caused most commonly by fungi known as dermatophytes (Trichophyton rubrum and Trichophyton mentagrophytes), and less commonly by yeasts (Candida albicans causes fingernail infections), and molds (Scopulariopsis, Fusarium). Infections caused by dermatophytes are generally limited to the nail, but may spread to the surrounding skin and cause inflammation. The four types of onychomycosis include distal and/or lateral subungual onychomycosis affecting the nail bed and nail plate; proximal subungual onychomycosis affecting the proximal nail fold with infection extending distally under the nail plate; superficial white onychomycosis affecting the top of the nail plate; and candidal onychomycosis affecting the nail and skin. Onychomycosis is difficult to treat, in that secondary skin infections including paronychia, and recurrent fungal infections of the nails or other parts of the body may occur. Oral medications such as Lamisil™ (terbinafine) or Sporanox™ (itraconazole) may produce adverse side effects in the liver, while topical treatments tend to be ineffective. Further, oral and topical medications work gradually, requiring several months to completely eliminate the infection.
IX Acne and Related Conditions
The term “acne” is a general term to denote inflammatory disorders of the pilosebaceous unit. Acne is a group of disorders whose initial pathology is the comedo and includes acne vulgaris (common acne), neonatal acne, infantile acne, and pomade acne. Acne commonly afflicts adolescents and young adults; however, there is growing number of patients who develop acne in their late twenties or thirties. There are data that suggest a familial or genetic tendency for patients to develop severe cystic or conglobate acne. Additionally, acne has been linked to endocrine disorders, especially those characterized by elevated levels of circulating testosterone or testosterone congeners. Exogenous agents that could exacerbate acne include medications e.g. iodides, anti-seizure, certain antibiotics and corticosteroids.
Acne is a chronic inflammatory disorder affecting the sebaceous glands. Acne lesions primarily involve the sebaceous glands located on the face, neck, chest and back. Both closed comedones (blackheads) and open comedones (whiteheads) are caused by hyperkeratinization of the infundibulum of the sebaceous duct. These keratinous plugs block the flow of sebum. These dilated ducts abound with the colonies of Propionibacterium acnes and other fat splitting organisms. The clinically evident open and closed comedones and the microscopic microcomedo are the signal lesions of acne. The acne process results from a cascade of events. First, at puberty a spike in androgen production heralds an increase in sebum production and begins the hyperkeratinization process causing microcomedones and sebum blockade. With this blockage, the number of resident follicular flora increases dramatically. These bacteria produce inflammatory products, which permeate through thin walls of dilated sebum-filled duct. Once in the perifollicular dermis, they trigger the body's own immune defenses (both acute and granulaomatous) to produce the characteristic inflammatory papules, pustules and nodules characteristic of inflammatory acne.
Increased sebum production; comedo formation, in which the follicular infundibulum hypercomifies, hyperkeratinizes, and hypodesquamates; colonization of the follicule by anaerobic Propionibacterium (mainly P. acnes); and the host's inflammatory response are generally believed to contribute to the development of acne. These four factors are interrelated. Sebum is comedogenic and causes inflammation by itself. The Propionibacterium has high lipolytic activity and liberates free fatty acids from sebum lipids, whereby the free fatty acids have been shown to cause marked inflammation. The microorganisms also produce other extracellular enzymes such as proteases and hyaluronidases, and chemotactic factors, which may be important in the inflammatory process. Aside from these factors, serum hormones, especially dehydroepiandrosterone sulfate, have been found to correlate with acne.
Acne treatments generally target the keratinous plugs in sebaceous ducts; large sebaceous glands producing excess sebum; increased numbers of resident follicular bacteria; and inflammatory response to chemical mediators passing through the follicular wall. Most acne treatments are directed at preventing inflammatory lesions, particularly the larger nodulo-cystic lesions which tend to be destructive and lead to permanent scarring. In general, visible comedones are the only minor cosmetic nuisances and do not lead to inflammatory lesions.
Topical products used to remove comedones (“comedolytics”) include tretinoin (Retin A™), adapalene 0.1% (Differin™), sodium sulfacetamide 10%/sulfur 5% (Sulfacet-R™), and salicylic acid 2%. A naturally occurring metabolite of Vitamin A, tretinoin or all-trans retinoic acid increases epidermal cell turnover and prevents the formation of new keratinous plugs. Application of tretinoin is normally once nightly. Although tretinoin is the most effective comedolytic, dryness, stinging and redness may occur, and improvement takes 6-8 weeks. Adapalene 0.1% is a topical retinoid-like tretinoin and is usually applied once nightly. Side effects include frequent scaling, burning, redness and dryness, and improvement takes 4-8 weeks. Sodium sulfacetamide 10%/sulfur 5% is both an antibacterial and comedolytic lotion, with improvement taking 4-8 weeks. Salicylic acid 2% exhibits mild activity.
For severe cystic or conglobate acne, isotretinoin (Accutane™), which is a metabolite of Vitamin A, is administered orally. Isotretinoin has effective anti-sebum activity, but is teratogenic (causing birth defects), and hepatotoxic (elevating triglycerides and total cholesterol and decreasing high-density lipoproteins). Other side effects include dry skin, dry eyes, itching, headaches, nosebleed, and photosensitivity. Improvement takes 4-5 months. Since estrogens also have anti-sebum activity, acne may also be treated with oral contraceptive pills.
Topical and/or oral antimicrobial agents may also be used to decrease bacteria that colonize the follicular duct. Topical agents include benzoyl peroxide (BP), and BP 5%/erythromycin 3% (Benzamycin™). BP is often tried first for both non-inflammatory and mild inflammatory acne, but can produce erythema and peeling, and improvement takes 1-2 months. Topical antibiotics include clindamycin and erythromycin, with improvements taking 1-2 months. Azelaic acid 20% (Azelex™) has mild antibacterial effects. Further, systemic antibiotics include tetracycline and its analogs (doxycycline and minocycline), which are used in low doses for years or until the end of the acne prone years. However, bacterial resistance may occur, such that the antibiotics need to be changed or substituted with BP.
Intralesional corticosteroids and topical nicotinamide have also been used to control a host's inflammatory response. There are no drugs that directly affect the inflammatory acne. The retinoids do have some anti-inflammatory properties, but these are poorly described. Topical steroid and even systemic steroids have been used to abort a severe flare of fulminant acne, but have undesirable side effects.
Treatments for Inflammatory Skin Conditions
While a range of treatments have been developed for inflammatory skin conditions, none are completely effective or free of adverse side effects. As outlined above, treatments for different inflammatory skin conditions typically include topical or oral steroids (e.g., for various types of eczema, acne, and erythema multiforme); ultraviolet light (e.g., for nummular eczema and mycosis fungoides); or other anti-inflammatory therapies. However, such treatments may be ineffective, provide only temporary relief, have deleterious side effects, or take months to treat. As an example, no treatment is uniformly effective for nummular eczema or stasis eczema. Current treatments for mycosis fungoides are only temporarily effective. Oral steroids have significant side effects, such that the severity of the skin disease must be carefully assessed. While short term treatment (a few days or weeks) with oral steroids is relatively safe, long term treatment (more than 3 months) may cause undesirable side effects including Cushing's syndrome, skin thinning, and increased susceptibility to infection. Improvements may be delayed, such as with the various acne treatments lasting several months.
While the patent literature reports that silver metal or silver salts such as silver nitrate, silver halides or silver sulphadiazine are among useful antibacterial agents for skin treatment, they have not, to the inventor's knowledge, been widely adopted for treatment of inflammatory skin conditions. In some inflammatory conditions, secondary infection is a possibility; thus, a treatment which contributes both anti-inflammatory and antimicrobial effects is advantageous. Further, there still exists a need for the treatment of inflammatory skin conditions including eczema, acne, and other related inflammatory skin conditions, with such a treatment being effective, lacking undesirable side effects, and showing improvement without a lengthy delay.